We read with interest the article by Elsayed et al. [1] describing a family with autosomal recessive congenital ataxia due to a homozygous 5-bp deletion in the β3-spectrin gene (SPTBN2). In-frame heterozygous variants of this gene had previously been identified as the cause of autosomal dominant adult-onset SCA5 (MIM#600224) (Suppl.Tab.1) [2,3,4]. The authors postulated the existence of SPTBN2 genotype-phenotype correlates, suggesting that loss of function mutations would act recessively, producing a severe congenital ataxic phenotype associated with cognitive impairment and variable additional neurological signs. This hypothesis was partially supported by three subsequent studies, reporting homozygous missense, nonsense and splicing SPTBN2 variants, all resulting in an analogous congenital ataxia syndrome, defined as SCAR14 (MIM#615386) (Suppl.Tab.1) [5,6,7]. Elsayed and colleagues [1] also mentioned a previously reported patient affected by a severe infantile-onset cerebellar ataxia with developmental delay, carrying the heterozygous missense variant c.1438C>T (p.R480W) in the SPTBN2 gene [8]. Based on previous literature data on heterozygous SPTBN2 mutation carriers (presenting the typical SCA5 phenotype of adult-onset, slowly progressive pure cerebellar ataxia), they speculated that either a second-site SCA5 modifier or an undetected SPTBN2 variant in trans (e.g., deep intronic or in a non-coding regulatory region) should contribute to the phenotypic manifestation.

In this regard, we would like to report an additional case of congenital severe cerebellar ataxia and intellectual impairment carrying the same SPTBN2 p.R480W variant. This is a 2-year-old girl, the third child of healthy non-consanguineous parents. She was born by cesarean section after an uncomplicated full-term pregnancy and was referred to the neuropsychiatric clinic because of generalized hypotonia, global developmental delay, and alternating esotropia. At age 12 months, she said her first words and got head control, but could not sit without support. Two months later, her developmental quotient was calculated to be 56. She progressively developed a cerebellar syndrome with gait ataxia and dysarthria. Brain MRI performed at age 1 year 10 months showed global cerebellar hypoplasia with enlarged interfolial spaces, in the absence of any brainstem or supratentorial abnormalities (Suppl.Fig.1A). Molecular analysis consisted of a next-generation sequencing (NGS) panel of 50 genes causative of different forms of non-progressive cerebellar ataxia (with the exclusion of Joubert Syndrome genes), using TruSeq Custom Amplicon (TSCA) technology on a MiSeq platform (Illumina, San Diego, CA, USA). As in the case reported by Jacob et al. [8], this child was heterozygous for SPTBN2 p.R480W missense variant (NM_006946). This variant was not detected in either of the unaffected parents, suggesting de novo occurrence (Suppl.Fig.1B). Potential heterozygous deletions involving one or more exons were ruled out using a custom script tool aimed at detecting significant differences in read depth from NGS data. The p.R480W variant (rs397514749) is not present in population databases, affects a highly conserved amino acid, and multiple in silico tools consistently predict it as deleterious on the gene product (Suppl.Fig.1C-D). Interestingly, Parolin-Schnekenberg and coworkers recently performed a genetic screening in a cohort of children diagnosed with ataxic cerebral palsy, and identified this same heterozygous variant in one case, confirming its pathogenicity using in vitro models [9]. Based on all these evidences, the variant can be classified as pathogenic according to ACMG guidelines.

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